Mutants only partially represent characteristics of calcium-release-activated calcium channel gating

被引:0
|
作者
Huo, Jun [1 ]
Lu, Ben-zhuo [2 ]
Dong, Hao [1 ,3 ,4 ,5 ]
机构
[1] Nanjing Univ, Kuang Yaming Honors Sch, Nanjing 210023, Peoples R China
[2] Chinese Acad Sci, Acad Math & Syst Sci, Univ Chinese Acad Sci, CEMS,LSEC,NCMIS,Sch Math Sci, Beijing 100190, Peoples R China
[3] Nanjing Univ, Inst Brain Sci, Nanjing 210023, Peoples R China
[4] Nanjing Univ, State Key Lab Analyt Chem Life Sci, Nanjing 210023, Peoples R China
[5] Nanjing Univ, Engn Res Ctr Prot & Peptide Med, Minist Educ, Nanjing 210023, Peoples R China
基金
中国国家自然科学基金;
关键词
Calcium-release-activated calcium channel; Gating mechanism; Molecular dynamics simulations; Mutant; Free energy profile; CRAC CHANNEL; ION SELECTIVITY; ORAI1; PERMEATION; MUTATIONS; STIM1;
D O I
10.1063/1674-0068/cjcp2111231
中图分类号
O64 [物理化学(理论化学)、化学物理学]; O56 [分子物理学、原子物理学];
学科分类号
070203 ; 070304 ; 081704 ; 1406 ;
摘要
Calcium-release-activated calcium (CARC) channels are one of the major pathways of calcium entry in non-excitable cells. Despite a decade or two of research, its regulatory mechanism is not yet thoroughly understood. The slow progress is due to the complexity of its pores (i.e., Orai) on one hand and the difficulty in capturing its regulatory complex on the other hand. As a result, possible gating mechanisms have often been speculated by exploring the structure and properties of constitutive open mutants. However, there is much debate about how they can truly reflect the gating of CRAC channels under physiological conditions. In the present study, we combined molecular dynamics simulations with free energy calculations to study three dOrai mutants (G170P, H206A, and P288A), and further calculated their current-voltage curves. Results show that these constructs adopt different approaches to maintain their conductive state. Meanwhile they have unique pore structures and distinctive rectification properties and ion selectivity for cations compared to wild-type pores. We conclude that although the mutants may partially capture the gating motion characteristics of wild-type pores, the information obtained from these mutants is likely not a true reflection of CRAC channel gating under physiological conditions.
引用
收藏
页码:915 / 924
页数:10
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